The association of Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma gene with serum osteoprotegerin levels in healthy Korean women

Recent evidences suggest that the activation of peroxisome proliferator-activated receptor (PPAR)-gamma, which is an important transcriptional factor in adipocyte differentiation, also plays an important role in the bone microenvironment. The objective of the study was to clarify whether Pro12Ala polymorphism was related to the serum OPG levels and bone mineral metabolism in healthy Korean women. In 239 Korean women (mean age 51 years), who participated in medical check-up program in a health promotion center, anthropometric measurements, lumbar spine and femoral neck bone mineral density (BMD), bone turnover markers, such as serum total alkaline phosphatase (ALP) levels, urine deoxypyridinoline levels, and 24-h urine calcium excretion were measured. Serum levels of OPG were measured with ELISA method. DNAs were extracted from the samples and the genotyping of the Pro12Ala polymorphism (rs1801282) in the PPAR-gamma gene was performed via an allelic discrimination assay using a TaqMan probe. In addition, we examined the haplotype analysis between two polymorphisms of PPAR-gamma gene, Pro12Ala in exon B and C161T in exon 6 (rs3856806). Allelic frequencies were 0.950 for Pro allele and 0.050 for Ala allele, which was in compliance with Hardy- Weinberg equilibrium, and there was no Ala12Ala genotype among the genotyped subjects. Mean serum OPG level was significantly lower (P=0.035), and serum total ALP was significantly higher (P=0.014) in the Pro12Ala genotype group compared with the Pro12Pro genotype group, which were consistently significant even after adjustment for weight, height, and serum follicle stimulating hormone (FSH). In multiple regression analysis with serum OPG as the dependent variable and age, weight, ALP, femoral neck BMD and Pro12Ala genotype included in the model, only Pro12Ala genotype was significant determinant of serum OPG level (beta=-0.136, P=0.035). The haplotype analysis with C161T polymorphism revealed that subjects with Ala and T alleles showed significantly lower serum OPG levels compared with those with Pro12Pro/CC genotype, which were consistently significant even after adjustment for age, weight, height and FSH (P=0.010). This result suggests statistically significant association of Pro12Ala polymorphisms with serum OPG levels in Korean females.

Change of serum ghrelin concentration according to severity of hepatosteatosis / 대한내과학회지

BACKGROUND: Recently, ghrelin has been reported to be associated with insulin resistance. Nonalcoholic fatty liver disease (NAFLD) is a condition in which insulin resistance relatively plays a pivotal role. The aim of this study was to evaluate the change of serum ghrelin concentration according to severity of hepatosteatosis. METHODS: Sixty five apparently normal male adults who underwent health screen examinations were classified into three groups, Group I: normal (27 subjects), Group II: mild (24 subjects) and Group III: moderate to severe fatty liver (14 subjects), according to ultrasonographic findings of liver. We analyzed the association between serum ghrelin concentration and severity of hepatosteatosis by ANOVA test. And the independent correlation between serum ghrelin concentration and insulin resistance related factors, HOMA (homeostatic model assessment), BMI (body mass index), WC (waist circumference), HC (hip circumference), WHR (waist to hip circumference ratio) were analyzed by multiple linear regression analysis. RESULTS: Serum ghrelin concentration tended to decrease according to severity of hepatosteatosis (Group I: 230.9+/-94.3, Group II: 195.2+/-97.2, Group III: 164.3+/-71.4 pmol/L). But this was statistically insignificant (p=0.081). The independent correlation between serum ghrelin concentration and insulin resistance related factors were not observed. CONCLUSIONS: Our study did not prove the correlation between insulin resistance related factors and serum ghrelin concentration in NAFLD according to severity of hepatosteatosis. However, we found a tendency to decrease serum ghrelin concentration according to severity of hepatosteatosis. So, further studies are required for certification these correlations.

The Effect of Oxidative Stress on the Proliferation and Differentiation of Human Bone Marrow Stromal Cell-Derived Osteoblasts / 대한내분비학회지

BACKGROUND: The objectives of our study were to assess the effects of oxidative stress on the proliferation, differentiation and apoptosis of human bone marrow stromal cell (BMSC)-derived osteoblasts and to explore pathways by which osteoblast cell apoptosis was induced. METHODS: Mononuclear cells including BMSCs were cultured to osteoblastic lineage. Different doses of hydrogen peroxide (H2O2) were added to the culture media. The colony forming units-fibroblastic (CFU-Fs) were stained with crystal violet and alkaline phosphatase (ALP). The MTT assay was done to see the effect of H2O2 on cell viability. The effect of H2O2 on osteocalcin gene expression was determined by RT-PCR. The matrix calcification measurement was performed. FACS analysis was performed to determine the osteoblasts apoptosis. Caspase-3, -8 and 9 activity assay and cytochrome c release were measured. RESULTS: The size and number of ALP (+) CFU-Fs were also decreased by H2O2 treatment. When compared with the control group, H2O2 significantly decreased the total number of cells of each culture well during MTT assay. H2O2 significantly diminished expression of osteocalcin mRNA. N-acetylcystein (NAC) blocked the diminution of cell viability and the inhibition of osteocalcin mRNA expression by H2O2. H2O2 reduced matrix calcification. FACS analysis revealed H2O2 increased percentage of apoptotic cells. Addition of H2O2 resulted in the increase of caspase-9 and -3 activity but not caspase-8, and release of cytochrome c to the cytosol. CONCLUSION: These data suggest that, in primary human BMSCs, oxidative stress inhibits proliferation of stromal cells and inhibits the differentiation to osteoblastic lineage. In addition, oxidative stress induces apoptosis of human BMSC-derived osteoblasts and this may be mediated by mitochondrial pathway of apoptotic signal.

Factors affecting serum levels of adipokines in Korean male patients with nonalcoholic fatty liver disease / 대한내과학회지

BACKGROUND: Adipokines are associated with various metabolic disorders including insulin resistance, obesity and dyslipidemia. Metabolic disorders have also been reported to be associated with nonalcoholic fatty liver disease (NAFLD). We aimed to estimate changes in serum adipokines levels according to the degrees of steatosis and to determine independent factors influencing serum adipokines levels in Korean male patients with NAFLD. METHODS: 65 Korean male patients were subjected. The degrees of steatosis were stratified into the three groups, Group I: normal liver (27 subjects), Group II: mild fatty liver (24 subjects) and Group III: moderate to severe fatty liver (14 subjects), according to ultrasonographic liver findings. The anthropometric parameters, fasting serum adipokine levels including leptin, adiponectin and resistin were measured in all subjects. The level of insulin resistance was estimated using the HOMA-IR. RESULTS: Serum leptin levels were significantly different among the three groups (mean+/-SD: Group I (2.052+/-1.071), Group II (2.879+/-1.016), Group III (4.457+/-1.965 ng/mL), p<0.001). Serum adiponectin and resistin levels were not significantly different among the three groups (p=0.184, p=0.649, respectively). BMI and HOMA-IR were independent factors of changes in serum leptin levels (p=0.026, p=0.001, respectively), but independent factors of changes in serum adiponectin and resistin levels were not observed. CONCLUSIONS: Our study support a indirect role to induce metabolic disorder for leptin in the pathogenesis of NAFLD, but do not support roles for adiponectin and resistin in the pathogenesis of NAFLD. BMI and HOMA-IR were only independent factors of changes in serum leptin levels.

The relationship between osteoprotegerin gene polymorphism and aortic calcification in Korean women / 대한내과학회지

BACKGROUND: Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the receptor activator of NF-kappa B ligand (RANKL). OPG has been shown to be an important inhibitor of osteoclastogenesis and arterial calcification in animal models. Recently, OPG has been proposed as a link molecule between osteoporosis and arterial calcification, but the relationship between OPG gene and cardiovascular system in human populations is unclear. Thus, the aim of this study was to investigate the relationship between OPG gene polymorphisms and aortic calcification in healthy Korean women. METHODS: We observed 251 healthy Korean women (mean age, 51.3+/-6.9 yr). We determined cardiovascular risk factors. Thoracic and abdominal aortic calcifications were examined by simple radiological methods. A163G, G209A, T245G, and T950C polymorphisms of OPG gene were analyzed by allelic discrimination using the 5' nuclease polymerase chain reaction assay. RESULTS: The frequency of mutant allele was increased in the aortic calcification (+) group as compared with aortic calcification (-) group (G209A, 28.6% vs. 18.7%, p=0.029; T950C, 75.9% vs. 65.4%, p=0.017). However, no significant relationship was found between OPG gene polymorphisms and serum OPG levels and cardiovascular risk factors. CONCLUSIONS: We observed that the OPG gene polymorphisms were partly associated with aortic calcification in healthy Korean women. Further studies are needed to clarify this relationship.

The Relationship Between Serum Adiponectin Level and Serum Alanine Aminotransferase Elevation in Korean Male with Nonalcoholic Fatty Liver Disease / 대한간학회지

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) comprises a large part of chronic liver diseases. Recently it was reported that adipokines are closely associated with the common risk factors for NAFLD, such as obesity, diabetes, dyslipidemia, and insulin resistance. We aimed to evaluate the changes in serum adiponectin, resistin and leptin concentrations related to alanine aminotransferase (ALT) elevations in Korean men with NAFLD. METHODS: We studies 38 men who were diagnosed with fatty liver by abdominal ultrasonography. None had a history of excessive alcohol consumption, autoimmune hepatitis, inherited or metabolic liver disease or viral hepatitis. The subjects were divided into two groups. One group had normal levels of ALT (n=28) and the other had increased ALT (n=10). We compared anthropometrical parameters, biochemical items and serum adipokine levels between these two groups. RESULTS: Serum adiponectin levels were lower in the increased ALT group than in the normal ALT group (3.89 +/- 1.77 vs 7.01 +/- 2.54 microgram/dL, P=0.001). But there were no significant differences in serum leptin and resistin levels between two groups (4.02 +/- 2.04 vs 3.26 +/- 1.41 ng/mL, p=0.245, 80.14 +/- 14.8 vs 80.5 +/- 11.34 ng/mL, P=0.937, respectively). Multiple linear regression analyses demonstrated that the serum adiponectin level is inversely correlated with serum ALT level and that the serum aspartate aminotransferase (AST) level is positively correlated with the serum ALT level. CONCLUSIONS: Our study shows that hypoadiponectinemia is associated with an ALT elevation in patients with NAFLD. Adiponectin may play an indirect role in the development of NAFLD.

Relationships between serum osteoprotegerin levels and insulin resistance, cardiovascular risk factors and bone metabolism in type 2 diabetic patients / 대한내과학회지

BACKGROUND: Osteoprotegerin (OPG) is a soluble glycoprotein which inhibits osteoclastogenesis through binding to receptor activator of nuclear factor-kappaB ligand (RANKL). OPG-knockout mice develop early-onset osteoporosis and arterial calcification. Recent studies report that serum OPG levels are elevated in diabetic patients with cardiovascular disease and are associated with the presence and severity of coronary artery disease. We examined the relationships between serum OPG levels and insulin resistance, bone metabolism and cardiovascular risk factors in diabetic patients. METHODS: In 84 diabetic patients (33 men, 51 women, mean age 56.7 years old) were studied. Blood pressure, body mass index (BMI), fasting blood glucose, postprandial 2-hour blood glucose, fasting insulin and lipid profiles were measured. Serum OPG levels were measured with sandwich ELISA method. Bone mineral density (BMD)s were checked and serum osteocalcin and urine deoxypyridinoline levels were checked as bone turnover markers. 24-hour urine microalbumin were checked and left ventricular mass index (LVMI) were evaluated with echocardiography. From simple chest X-ray, the presence of aortic calcification were confirmed by a trained radiologist. Homeostatic model assessment (HOMA)-insulin resistance (IR), quantitative insulin sensitivity check index (QUICKI) were calculated as insulin resistance indices. RESULTS: Serum OPG levels were positively correlated with age, LVMI, HOMA and negatively correlated with lumbar spine BMD and QUICKI. After adjustment for age, only LVMI showed persistent correlation with serum OPG levels and when multiple regression analysis was performed with LVMI as the dependent variable, BMI and OPG were the significant predictors of LVMI (R2=0.054, p=0.012). Dividing the subjects into 3 groups according to 24-hour urine microalbumin levels, mean values for serum OPG levels increased as 24-hours urine microalbumin levels increased, but without statistical significance. Mean serum OPG levels were higher in patients with aortic calcification, without statistical significance. CONCLUSION: Serum OPG levels were positively correlated with insulin resistance indices and negatively correlated with lumbar spine BMD in diabetic patients, suggesting a compensatory mechanism to counteract bone loss progression. Serum OPG levels were independent predictor for LVMI in diabetic patients, warranting further research on OPG as the marker for future cardiovascular mortality in diabetic patients.

The Changes in the Serum RANKL and OPG levels after Bone Marrow Transplantation: Association with Bone Mineral Metabolism / 대한내분비학회지

BACKGROUND: The loss of bone mass is usually detected after bone marrow transplantation(BMT), particularly during the early post-transplant period. We recently reported that enhanced bone resorption following BMT was related to both the steroid dose and increase in IL-6. It was also suggested damage of the marrow microenvironment due to myeloablation and changes in bone growth factors contribute to post-BMT bone loss. Recently, the interactions of OPG and RANKL have been reported to be crucial in osteoclastogenesis and therefore in bone homeostasis. There are few data on the changes in RANKL/OPG status during the post-BMT period. This study investigated the changes in the levels of RANKL and OPG during the post-BMT period, and also assessed whether the changes in these cytokine levels actually influenced bone turnover and post-BMT bone loss. METHODS: We prospectively investigated 110 patients undergoing allogenic BMT and analyzed 36 (32.4+/-1.3 years, 17 men and 19 women) where DEXA was performed before and 1 year after the BMT. The serum bone turnover marker levels were measured before and 1, 2, 3, 4 and 12 wks, 6 Ms, and 1 yr after the BMT. The serum sRANKL and OPG levels were measured in all patients before and 1, 3 and 12 wks after the BMT. RESULTS: The mean bone losses in the lumbar spine and total proximal femur, which were calculated as the percent change from the baseline to 1 yr, were 5.2(P<0.01) and 11.6%(P<0.01), respectively. The mean serum ICTP, a bone resorption marker, increased progressively until 3 and 6 months after the BMT, but decreased gradually thereafter, reaching the basal values after 1 year. The serum osteocalcin levels decreased progressively until 3 wks after the BMT, then increased transiently at 3 and 6 Ms, but returned to the basal level by 1 yr. The serum sRANKL and OPG levels had increased significantly by weeks 1 and 3 compared with the baseline(P<0.01), but decreased at 3 months. The sRANKL/OPG ratio increased progressively until 3 weeks, but then decreased to the basal values. During the observation period, the percent changes from the baseline in the serum RANKL levels and RANKL/OPG ratio showed positive correlations with the percent changes from the baseline serum ICTP levels. Patients with higher RANKL levels and RANKL/OPG ratio during the early post-BMT period lost more bone mass at the lumbar spine. CONCLUSION: In conclusion, dynamic changes in the sRANKL and OPG levels were observed during the immediate post-BMT period, which were related to a decrease in bone formation and loss of L-spine BMD during the year following the BMT. Taken together, these results suggest that increased sRANKL levels and sRANKL/OPG ratios could be involved in a negative balance in bone metabolism following BMT.

Relationship between Circulating Osteoprotegerin and Cardiovascular Risk Factors in Women / 대한내분비학회지

BACKGROUND: Osteoprotegerin(OPG) is a recently identified cytokine, which acts as a decoy receptor for the receptor activator of NF-B ligand(RANKL). OPG has been shown to be an important inhibitor of osteoclastogenesis and arterial calcification in animal models. Recently, OPG has been proposed as a link molecule between osteoporosis and arterial calcification. However, the relationship between circulating OPG levels and cardiovascular disease in human populations is unclear. Thus, the aim of this study was to investigate the relationship between circulating OPG levels and cardiovascular risk factors in women. METHODS: The subjects were 286 women, with a mean age of 51.5 yr. The blood pressure, body mass index(BMI) and waist to hip ratio(WHR) were examined and the serum concentrations of OPG determined by ELISA. The fasting glucose levels, serum lipid profiles and follicle stimulating hormone (FSH) were measured by standard methods. RESULTS: A significant association was observed between the serum OPG levels, age and WHR(r=0.134, P<0.05). Also, the serum OPG levels were significantly correlated with the serum total cholesterol and low density lipoprotein cholesterol levels(r=0.175, P<0.01; r=0.176, P<0.01). Conversely, there was a nonsignificant relationship between the serum OPG levels, blood pressure and fasting glucose levels. The mean serum OPG levels were found to be about 11% greater in post-than premenopausal women(mean+/-SD, 1358.5+/-380.0 vs. 1228.8+/-407.7pg/mL, respectively(P<0.001). There was a significant association between the serum OPG and serum FSH levels(r=0.176, P<0.01). CONCLUSION: In conclusion, our data show that the levels of circulating OPG are partially associated with the cardiovascular risk factors and female hormonal status in healthy women. These data suggest that OPG may be an important paracrine factor of cardiovascular disease in human female populations.

Relationship between serum osteoprotegerin levels and bone mineral metabolism in women / 대한내과학회지

BACKGROUND: Osteoprotegerin (OPG) is a recently identified cytokine that acts as a decoy receptor for the RANK ligand. OPG has been shown to be an important inhibitor of osteoclastogenesis in animal models. The relationship between circulating OPG levels and female bone status in human populations is unclear. Thus, the aim of this study was to investigate the relationship between circulating OPG levels and bone mineral metabolism in Korean women. METHODS: ubjects were 287 women aged 37~73 (mean age, 51.5 yr). Serum concentrations of OPG were determined by ELISA. Biochemical markers of bone turnover and follicle stimulating hormone (FSH) were measured by standard methods. Bone mineral density at lumbar spine and femur neck were measured by dual energy X-ray absorptiometry. RESULTS: e observed a significant positive association between circulating OPG levels and urine calcium excretion (r=0.128; p<0.05). Although circulating OPG levels were not significantly correlated to urine deoxypyridinoline levels (r=0.105; p=0.076), but there was a weak trend in it. We found that mean OPG levels were about 11% greater in postmenopausal women (mean +/- SD, 1358.5 +/- 380.0 pg/mL) than in premenopausal women (1228.8 +/- 407.7 pg/mL; p<0.001). There was a significant positive relationship between circulating OPG levels and serum FSH levels (r=0.172; p<0.01). There was a non-significant relationship between circulating OPG levels and bone mineral density at lumbar spine and femur neck. CONCLUSION: In conclusion, our data shows that the circulating OPG levels are associated with urine calciumexcretion and serum FSH levels in Korean women. These data suggest that OPG may be an important paracrine mediator of female bone metabolism in human populations.

Relationship between serum thyroid stimulating hormone levels and serum osteoprotegerin levels and bone mineral density in healthy men / 대한내과학회지

BACKGROUND: In untreated hyper or hypothyroidism decreased bone mineral density (BMD) has been demonstrated. Studies on fracture risk in patients with hyper or hypothyroidism have reported an increased risk of osteoporotic fractures. The osteoporosis associated with thyroid dysfunction is traditionally viewed as a secondary consequence of altered thyroid function. Recently, there was a report about direct effects of thyroid stimulating hormone (TSH) on both components of skeletal remodeling, osteoblastic bone formation, and osteoclastic bone resorption, mediated via the TSH receptor found on osteoblast and osteoclast precursors. Thus, the aim of this study was to investigate the relationship between serum TSH levels, and osteoprotegerin (OPG)/ receptor activator of NF-B ligand (RANKL) system and bone mineral density in healthy men with euthyroid function. METHODS: We observed 75 korean men (mean age, 54.5 yr) with euthyroid function. Serum concentrations of TSH, free thyroxine, total testosterone, estradiol, insulin-like growth factor I (IGF-I) and biochemical markers of bone turnover were measured by standard methods. Enzyme-linked immunosorbent assay determined serum concentrations of OPG and RANKL. BMD at lumbar spine and femoral neck were measured by dual energy X-ray absorptiometry. RESULTS: When the BMD at lumbar spine or femoral neck were examined as the dependent variable in multiple regression analysis, serum total testosterone, estradiol and IGF-I levels were identified as a significant predictor for BMD at lumbar spine, and only serum IGF-I levels for BMD at femoral neck. For Serum OPG or RANKL levels as the dependent variable, serum TSH, estradiol levels and BMD at femoral neck were identified as a significant predictor for serum OPG levels, and only serum estradiol levels for serum RANKL levels. CONCLUSION: Our data shows that the serum TSH levels are independently associated with serum OPG levels in healthy men with euthyroid function, but not associated with BMD. Our observations suggest that serum TSH levels are partly related with resorptive mechanism of bone metabolism in men, but further research is needed to establish its relation with TNF and other pro-resorptive cytokines.

Association between serum osteoprotegerin levels and disease severity and cardiovascular risk factors in patients with coronary artery diseases / 대한내과학회지

BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that acts as a decoy receptor to receptor-activated RANKL (receptor-activated NF-kappa B ligand) and inhibits the differentiation of osteoclasts. OPG knock-out mice showed severe osteoporosis and aortic calcification and high serum OPG levels have been shown to predict future cardiovascular mortality in old Caucasian females. We measured serum OPG levels in coronary artery disease patients, compared serum OPG levels among different groups according to the number of stenotic vessels and observed the correlation with aortic calcification and cardiovascular risk factors. METHODS: One hundred subjects were enrolled in which coronary angiograms were performed due to chest pain in Kangbuk Samsung Hospital from April to August, 2003 (59 males, 41 females, mean age 56.9 +/- 11.9 yrs). Blood pressure, body mass index, fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels were measured in every subject. Cardiac echocardiograms were checked in 82 subjects and left ventricular mass indices (LV mass index) were calculated. Serum OPG levels were measured with enzyme-linked immunosorbent assay (ELISA) method. The presence of calcifications in aortic knob was checked in simple chest X-ray. RESULTS: Subjects were divided in 4 groups according to the number of stenotic vessels (significant stenosis>or=50%); 45 subjects in normal group, 30 in 1-vessel disease group, 15 in 2-vessel disease group and 10 in 3-vessel disease group. Mean value for age was significantly different among groups (p<0.01). Mean serum HDL-cholesterol level of normal group was higher than that of 1-vessel disease or 2-vessel disease group (p<0.05). Serum OPG levels increased significantly as the number of stenotic vessels increased and in post-hoc analysis, mean serum OPG levels were higher in 3-vessel disease group than normal or 1-vessel disease groups (p<0.05). Age, LV mass index and number of stenotic vessels showed significantly positive correlation with serum OPG levels, although only number of stenotic vessels showed persistently significant correlation after adjustment for age. There were no differences of serum OPG levels according to the presence of fasting hyperglycemia or aortic calcifications. CONCLUSION: Serum OPG levels increased as the number of stenotic coronary arteries increased and showed positive relationships with age, LV mass index. OPG seems to be elevated as a compensatory mechanism to the progression of atherosclerosis in humans.

The effects of C161->T polymorphisms in exon 6 of peroxisome proliferator-activated receptor-gamma gene on insulin resistance and the prevalence of metabolic syndrome in healthy korean subjects / 대한내과학회지

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)gamma is a member of nuclear receptor family, known to be involved mainly in adipocyte differentiation and suggested to play an important role in the pathogenesis of insulin resistance and diabetes. Although PPAR gamma Pro12Ala polymorphism has been massively studies under the hypothesis that it could have a protective effect against the development of diabetes, studies on the association of other PPAR gamma polymorphisms with insulin resistance and diabetes are scarce. We investigated the frequencies of PPAR gamma exon 6 C->T substitution in healthy Koreans and the correlations between different genotypes and insulin resistance and the prevalence of metabolic syndrome. METHODS: In total 335 Korean adults (37-73 years, mean age 52 +/- 7 years, 72 males, 263 females), body mass indices (BMI, Kg/m2) were calculated from height and weight measurements and blood pressure, fasting blood glucose, fasting insulin, serum lipid profiles were measured. Homeostatic model assessment (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated as insulin resistance indices. Metabolic syndrome was diagnosed according to Adult Treatment Panel (ATP) III guidelines, substituting waist circumference with BMI. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was done in all blood samples and statistical analysis were performed among different genotypes CC, CT and TT. RESULTS: The frequency of CC genotype was 64.5%, 31.6% for CT and 3.9% for TT genotype and the frequency of C allele was 0.803 and 0.197 for T allele, which was in Hardy-Weinberg equilibrium (p>0.05). There were no differences in the mean values of age, percent body fat (%), blood pressure, fasting blood glucose level, fasting insulin levels and HOMA, QUICKI and lipid battery among different genotypes (p>0.05). The prevalences of metabolic syndrome were not different among different genotypes, however, when prevalences of each components of metabolic syndrome was compared individually, the prevalence of fasting hyperglycemia (>or=110 mg/dL) was higher in group with T allele than group with CC genotype (pT polymorphism in Korean people was similar to that in caucasians. Although insulin resistance indices, BMI, prevalence of metabolic syndrome were not different among different genotypes, the fact that the prevalence of fasting hyperglycemia was higher and that of low HDL-C was lower in group with T allele suggests the role of this polymorphism in negative way in glucose metabolism and in positive way in atherosclerosis, which needs further investigation.

The Effects of C161-->T Polymorphisms in Exon 6 of Peroxisome Proliferator-Activated Receptor- Gene on Bone Mineral Metabolism and Serum Osteoprotegerin Levels in Healthy Korean Middle-aged Men / 대한내분비학회지

BACKGROUND: The peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor family known to be involved in adipocyte differentiation. Recent studies have revealed the inhibitory role of PPAR in osteoblastogenesis, which suggests its possibility as a candidate gene for osteoporosis. The frequency of C161-->T substitution in exon 6 of PPAR was observed in Korean men and the association of different genotypes with bone turnover markers, bone mineral density (BMD) and serum osteoprotegerin (OPG), which play inhibitory roles in osteoclastogenesis, examined. METHODS: In 72 healthy Korean men (mean age 54.5 6.4 yrs; range 42~69 yrs), anthropometric measurements, and lumbar spine and femoral neck BMD, and bone turnover markers, such as alkaline phosphatase (ALP), serum calcium, phosphorus, osteocalcin and cross-linked C-telopeptides of type I collagen (ICTP) measurements were performed. The levels of serum testosterone, estradiol and insulin-like growth factor (IGF-I), and those of serum OPG levels, were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) method. The DNAs were extracted from the samples, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the sequencing of the products were performed to confirm the substitution. RESULTS: The allele frequencies were 0.799 and 0.201 for the C and T allele, respectively, which were in Hardy-Weinberg equilibrium (p=0.80). Subjects with the CT genotype were older and those with the T allele showed higher blood pressure levels and lower body mass indices (p0.05). The levels of serum testosterone, estradiol, IGF-I and OPG were not different among the different genotype groups (p>0.05). The lumbar, femoral neck BMD (g/cm2) and T scores were significantly lower in subjects with T alleles, and those with CT genotypes showed the lowest BMD values (pT substitution in exon 6 of the PPAR gene in Korean men were similar to those observed in other races, and those with the T alleles showed significantly lower BMD values. These data imply the PPAR gene might be a candidate gene for the pathogenesis of osteoporosis

Factors associated with bone mineral density in Korean middle-aged men / 대한내과학회지

BACKGROUND: Osteoporosis is a growing health problem not only in women but also in men. This cross-sectional study examined the association of anthropometric, lifestyle and hormonal factors with bone mineral density (BMD) in 152 healthy Korean middle-aged men. METHODS: Smoking habits and alcohol consumption were assessed from an interview. Serum testosterone, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels were measured by radioimmunoassay. GH stimulating tests were performed with ingestion of 500 mg of L-dopa. BMD was measured at the lumbar spine and femur neck using dual-energy X-ray absorptiometry. RESULTS: 3.9% of middle-aged men were osteoporotic and 28.3% were osteopenic at lumbar spine site, and 5.9% were osteoporotic and 45.4% were osteopenic at femur neck site. Lumbar spine BMD correlated significantly with body mass index (BMI, r=0.301, p<0.001). Femur neck BMD correlated significantly with BMI (r=0.314, p<0.001), age (r=-0.209, p<0.01) and serum IGF-1 level (r=0.267, p<0.01). Osteoporotic men at Lumbar spine BMD had significant difference in BMI and smoking habits (83.3% vs. 29.1%, p<0.05) than normal BMD. Also, osteoporotic men of femur neck BMD had significant difference in age, BMI and serum IGF-1 levels (192.9 g/L vs. 268.4 g/L, p<0.01). CONCLUSION: Overall, 32.2~51.3% were osteopenic in Korean middle-aged men. We suggest that higher age, lower BMI, smoking habits and lower serum IGF-1 levels are risk factors for lower BMD in men. But, Serum testosterone and GH were not correlated with BMD in men.

Serum Insulin-Like Growth Factor I and Its Relating Factors in Healthy Korean Adults Aged over 40 Years

BACKGROUND: There is a clinical need for a reference value based on healthy adults in Korea. The aim of this study was to define IGF-1 concentration in healthy Korean adults and to investigate the factors relative to IGF-1 level. METHODS: By reviewing the medical records of a hospital in Korea, healthy 112 men and 109 women aged over 40 years were studied. We determined the serum IGF-1 levels of both groups according to age, sex, health behaviors, lipid profile, bone mineral density, serum albumin, waist circumference, body mass index, total testosterone, and FSH. RESULTS: IGF-1 had no sexual difference in any age group (258.7+/-84.3 ng/mL for men, 263.7+/-86.8 ng/mL for women), but correlated negatively with age (r=-0.43 and -0.35 for men and women, respectively). The mean decline was 49.6 ng/mL and 43.9 ng/mL per 10 years for men and women, respectively. IGF-1 correlated positively with serum albumin, total cholesterol, and bone mineral density of spine and femur neck. The multiple regression analysis showed that the most powerful factors influencing IGF-1 level was serum albumin (R2; 0.13) followed by age, bone mineral density of femur neck, and total cholesterol. CONCLUSION: We present a reference value for IGF-1 in healthy Korean adults aged over 40 years. The most powerful factor influencing IGF-1 level was serum albumin.

The relationship between urinary sodium excretion and bone mineral metabolism of climacteric women in Korea / 대한내과학회지

BACKGROUND: High oral intake of sodium is known to increase urinary calcium excretion in hypercalciuria and renal-stone formers, and there is well-documented correlation between urinary sodium and calcium excretion in 24-hour urine collections from normal subjects and postmenopausal women. The present study was aimed to investigate relationship between urinary sodium excretion and bone mineral metabolism of climacteric women in Korea. METHODS: We measured 24-hour urinary sodium, calcium, and creatinine level; serum osteocalcin level, serum alkaline phosphatase (ALP) level, serum follicular stimulating hormone (FSH) level; urine deoxypyridinoline (DPD) level; and bone mineral density (BMD) in 430 climacteric women in Korea (331 postmenopausal and 99 premenopausal women). RESULTS: The postmenopausal women had higher (p<0.05) value for mean urinary sodium to creatinine ratio of 0.225+/-0.078 mmol/mg vs. 0.209+/-0.061 mmol/mg and higher (p<0.001) value for mean urinary calcium to creatinine ratio of 0.261+/-0.125 mg/mg vs. 0.209+/-0.081 mg/mg than the premenopausal women. Significant positive correlation was noted between urinary sodium to creatinine ratio and urinary calcium to creatinine ratio (r=0.426, p<0.001). Negative correlation was found between urinary sodium to creatinine ratio and femur neck BMD (r=-0.099, p<0.05). Although urinary sodium to creatinine ratio was not significantly correlated to serum FSH level (r=0.066, p=0.088), serum ALP level (r=0.067, p=0.083), urine DPD level (r=0.077, p=0.056), and lumbar BMD (r=-0.067, p=0.083), but there is a weak trend in it. CONCLUSION: There is not only an increase in urinary sodium excretion at postmenopausal women, but also an increase in the urinary calcium excretion. It seems that subjects with a high urinary sodium excretion show a higher urinary calcium excretion that may have some effect on bone mineral metabolism. However, further studies are required to establish whether urinary sodium excretion have a direct effect on bone mineral metabolism of climacteric women in Korea.

The short-term effects of low-dose estrogen and micronized progesterone on bone turnover markers and serum lipid profiles in postmenopausal women / 대한내과학회지

BACKGROUND: Hormone replacement therapy in postmenopausal women is widely used for the relief of menopausal symptoms and the prevention of bone loss. But, it has been reported that many women discontinue hormone replacement therapy within early period, because the women suffer from breast pain, bleeding and weight gain. Also, further adverse influence of hormone replacement therapy on cardiovascular risk and breast cancer has been suggested. There are many controversies due to conflicting data of that. Recent studies suggest that low-dose estrogen provide bone benefits and micronized progesterone have favorable effects on lipid metabolism and breast density. This clinical trial evaluated the short-term effects of low-dose estrogen and micronized progesterone on bone turnover markers and serum lipid profiles in postmenopausal women. METHODS: This was a 12-week study in which 90 postmenopausal women received hormone replacement therapy. Participants were assigned in equal numbers to the following groups: (1) daily treatment with 0.625 mg conjugated equine estrogens (CEE) with medroxyprogesterone acetate MPA 2.5 mg to 5 mg, daily or cyclically; (2) daily treatment with 0.625 mg CEE with micronized progesterone (MP) 100 mg to 200 mg, daily or cyclically; (3) daily treatment with 0.3 mg CEE with MP 100 mg to 200 mg, daily or cyclically. Changes in bone turnover markers and serum lipid profiles were assessed. RESULTS: At 12-week, all treatment groups significantly improved bone turnover markers and serum lipid profiles, specifically serum alkaline phosphatase, serum osteocalcin, urine deoxypyridinoline and serum high density lipoprotein cholesterol level. CEE 0.625/MPA and CEE 0.625/MP significantly decreased serum low density lipoprotein cholesterol level. CEE 0.625/MPA significantly increased serum triglyceride level. CEE 0.625/MPA produced greater decreases in serum alkaline phosphatase level than CEE 0.625/MP and CEE 0.3/MP. CEE 0.625/MP produced greater increases in serum high density lipoprotein cholesterol level than CEE 0.625/MPA. CEE 0.625/MPA produced greater increase in serum triglyceride level than CEE 0.3/MP. CONCLUSION: Low-dose estrogen and MP generally improved bone turnover markers and serum lipid profiles. But, MP produced lesser favorable effects on a part of bone turnover markers. MP produced significantly greater increases in serum high density lipoprotein cholesterol than that of MPA. And Low-dose estrogen produced significantly lesser increases in triglyceride than that of conventional dose.

The Changes of Serum Growth Factors after Hematopoietic Stem Cell Transplantation: Impact on Bone Mineral Metabolism / 대한내분비학회지

BACKGROUND: A loss of bone mass is usually detected after a bone marrow transplantation (BMT), especially during the early post-transplant period. We recently reported that enhanced bone resorption following a BMT was related to both the steroid dose and the increase in IL-6. We also suggested damage to the marrow stromal microenvironment, by myoablation, partly explains the impaired bone formation following a BMT. It is well known that some growth factors play important role in bone growth and osteogenesis. However, the pathogenetic role of bone growth factors in post-BMT bone loss is unknown and data on the changes in the growth factors, in accordance with bone turnover markers and bone mineral density (BMD) changes are scarce. We investigated changes in bone growth factors such as IGF-I (Insulin-like growth factor-I), fibroblast growth factor-2 (FGF-2) and Macrophage colony stimulating factor (M-CSF), during the post-BMT period, and assessed whether the growth factor changes influenced the bone turnover and post-BMT bone loss. The present study is the first prospective study to describe the changes in bone growth factors following a BMT. METHODS: We prospectively investigated 110 patients undergoing a BMT, and analyzed 36 patients (32.4+/-1.3 years, 17 men and 19 women) whose BMDs were measured before, and 1 year after, the BMT. The serum biochemical markers of bone turnover were measured before, 1, 2, 3 and 4 weeks, 3 and 6 months, and 1 year, after the BMT. The serum FGF-2, IGF-I and M-CSF levels were measured before and 1 and 3 weeks, and 3 months after the BMT. The correlation between the changes of growth factors and various bone parameters was analyzed. RESULTS: The mean bone losses in the lumbar spine and total proximal femur, calculated as the percentage change from the baseline to the level at 1 year, were 5.2 (p<0.05) and 11.6% (p<0.01), respectively. The serum type I carboxyterminal telopeptide (ICTP), a bone resorption marker, increased progressively until 6 months after the BMT, but thereafter decreased, to the base value after 1 year. Serum osteocalcin, a bone formation marker, decreased progressively, until 3 weeks after the BMT but then increased transiently, and finally returned to the base level at 1 year. The serum IGF-I and FGF-2 also decreased progressively until 3 weeks and 1 week after the BMT, respectively, then increased to the base values at 3 months. The serum M-CSF increased briskly at 1 week post-BMT, then decreased to the base level. There were positive correlations between the percentage changes from the baseline proximal femur BMD and the IGF-I levels 3 weeks and 3 months (r=0.52, p<0.01, r=0.41, p<0.05) post BMT. A Significant correlation was found between the IGF-I and osteocalcin levels pre-BMT, and 3 weeks after the BMT. Another positive correlation was found between the M-CSF and the ICTP levels at 3 weeks post BMT (r=0.54, p<0.05). CONCLUSION: In conclusion, there were significant changes in the serum IGF-I, FGF-2 and M-CSF levels in the immediate post-BMT period, which were related to a decrease in bone formation and loss in the proximal femoral BMD during the year following the BMT

The Skeletal Site-Differential Changes in Bone Mineral Density Following Bone Marrow Transplantation: 3-Year Prospective Study

Loss of bone mass is usually detected after bone marrow transplantation (BMT) during the early post-transplant period. However, little is known about the long-term effects of BMT on bone metabolism. We have prospectively investigated 11 patients undergoing BMT. Bone mineral density (BMD) was measured before BMT, and 1, 2, and 3 yr after BMT. Serum markers of bone turnover were serially measured before BMT and 1, 2, 3, 4, and 12 weeks, 6 months, and 1 yr after BMT. The mean change in the lumbar spine (L2-4) BMD, calculated as the percent change from the baseline to the level at 1, 2, and 3 yr was -4.7% (NS), -1.1% (NS), and +6.4% (p<0.05), respectively. The mean change in the total proximal femur BMD from the baseline to the level at 1, 2, and 3 yr was -8.5% (p<0.01), -8.7% (p<0.05) and -5.6% (p<0.05), respectively. In summary, there was little decline in lumbar BMD at 1 yr following BMT and gradual recovery until 3 yr. In contrast, femoral BMD decreased much more than the lumbar area at 1 yr and did not recover until 3 yr. The mechanism of skeletal site-selective differences in the changes of BMD needs to be elucidated.